Clin Kidney J (2012) 5: 412–415
doi: 10.1093/ckj/sfs091
Original Article
Solid renal tumours of collecting duct origin in patients on chronic
lithium therapy
Maarten B. Rookmaaker1, Heleen A.J.M. van Gerven2, Roel Goldschmeding3 and Walther H. Boer1
1
Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands, 2Department of
Pathology, University Medical Center Utrecht, Utrecht, The Netherlands and 3Department of Old-Age Psychiatry, GGZ Ingeest,
Haarlem, The Netherlands
Correspondence and offprint requests to: Maarten B. Rookmaaker; E-mail: [email protected]
Abstract
Background. Lithium (Li) is an invaluable drug for the treatment of bipolar disorder. Long-term Li
use is associated with renal complications including the formation of uncomplicated renal cysts
caused by proliferation and expansion of collecting duct (CD) cells. We report six patients with
complicated renal cysts in the context of Li nephropathy.
Methods. Over a time period of 15 years, we have identified six patients with one or more solid
renal tumours in our population of approximately 50 patients with chronic Li nephropathy. In this
study we describe the clinical and pathological characteristics of these Li-related tumours.
Results. All patients were on Li therapy for over 10 years and suffered from varying degrees of
Li nephropathy. The tumours were all of CD origin and comprised both oncocytomas and
collecting duct carcinomas. The CD carcinomas differed from the very rare “classical” CD cell
carcinomas in histological appearance, multifocal presentation and non-aggressive clinical
behaviour
Conclusions. The increased incidence of CD derived tumours and atypical presentation of CD cell
carcinomas in patients with chronic Li nephropathy suggests that Li predisposes to the development of these tumours. We hypothesize that prolonged stimulation of CD cell proliferation and
expansion by Li not only causes cyst formation, but can eventually induce the formation of adenomas and carcinomas. Increased awareness of a possible relationship between chronic Li
therapy and renal neoplasms, will enhance the knowledge on epidemiology, clinical behavior and
optimal therapy for the Li-related renal neoplasms.
Keywords: cancer; cyst; lithium
Introduction
Lithium (Li) is an invaluable drug for the treatment of
bipolar disorder, with 1:500 people using Li in Western
societies. Chronic Li use is associated with several renal
complications. Renal diabetes insipidus occurs in up to
40% of the patients and ∼20% develop chronic tubulointerstitial nephritis that is associated with slowly progressive renal failure. A third aspect of chronic renal Li toxicity,
acquired polycystic kidney disease, has received little attention to date. Animal experiments have shown that Li
induces a proliferative response in the kidneys, specifically in the CD, causing tubular dilation and cyst formation [1]. In patients with lithium nephropathy,
abundant renal cysts are found using magnetic resonance imaging (MRI) and ultrasound [2]. In addition,
dilation of CD and cyst formation are distinguishing features in kidney biopsies of these patients [3]. Until now,
however, only uncomplicated renal cysts have been attributed to chronic Li use. Here, we report for the first
time that complicated solid renal masses can occur in
the context of Li nephropathy and show that these
tumours are of CD origin.
Cases
Over a time period of 15 years, we have identified six
patients with one or more solid renal tumours in our
population of ∼50 patients with chronic Li nephropathy
(Table 1). All patients were on Li therapy for more than
10 years and suffered from varying degrees of chronic
renal failure and renal diabetes insipidus. The renal
tumours were incidental findings during work up for renal
dysfunction (Patients 1, 4 and 5) or upon analysis of nonspecific abdominal complaints (Patients 2, 3 and 6). The
abdominal scans made to exclude regional metastases
showed multiple uncomplicated renal cysts in all patients
(Figure 1). In addition, a complicated cyst was found in
the contralateral kidney in one patient (Patient 4).
Histological evaluation demonstrated that all tumours
were of collecting duct (CD) origin (Table 2). In three
© The Author 2012. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
For permissions, please email: [email protected].
Solid renal tumours of CD in patients on chronic lithium therapy
413
Table 1. Patient characteristics
Patient
no.
Age
(years)
Sex
Li use
(years)
Plasma creatinine
[µmol/L (mg/dL)]
1
69
M
17
444 (5.0)
2
71
F
30
125 (1.4)
3
59
M
12
133 (1.5)
4
70
M
30
765 (8.7)
5
61
M
15
135 (1.5)
6
65
F
41
135 (1.5)
Radiological findings
Intervention
Lithium
Follow-up
Solid tumour L kidney
(4.5 cm)
Solid tumour R
kidney
(4.0 cm)
Solid tumour R
kidney
(3.0 cm)
Solid tumour L kidney
(3.0 cm), complicated
cyst R kidney
Solid tumour L kidney
(3.5 cm)
Solid tumour R
Kidney
(2.6 cm)
Nephrectomy,
haemodialysis
Partial nephrectomy
Continued
Continued
1 year, died of
unrelated cause
5 years, died of
unrelated cause
Nephrectomy
Continued
4 years, no
recurrence
Biopsy tumour L kidney,
radiological follow-up
Stopped
2 years, no growth
of lesions
Biopsy, awaiting surgery
Continued
Biopsy, radiological
follow-up
Continued
4 months, no
tumour growth
4 months
Fig. 1. Typical MRI of a CD tumour in a patient on chronic lithium therapy.
A large tumour can be seen in lower pole of the left kidney (arrow). In
addition, numerous renal cysts are present in both kidneys (open arrows).
Table 2. Tumour characteristics
Patient
no.
Tumour,
no.
1
1
CD
carcinoma
2
1
2
Oncocytoma
CD
carcinoma
CD
carcinoma
Histology
3
1
4
1
Oncocytoma
5
1
CD
carcinoma
6
1
Oncocytoma
CK
19
Vimentin
Other markers
present
+
+
CK8, 18
(CAM5.2), KL1;
CK HMW; EMA
+
+
+
+
CK8, 18
(CAM5.2); CD15
CK8, 18
(CAM5.2); CK
HMW; CD15
+
+
EMA; CD15; CK
HMW; CK7;
CD10; Ecadherin
CK, cytokeratin; EMA, epithelial membrane antigen; CK HMW, highmolecular-weight cytokeratin.
patients, histology and immunohistochemistry showed
the presence of a CD cell carcinoma (Patients 1, 3 and 5;
Figure 2). In the three other patients, the tumours had
the typical histological appearance of a renal oncocytoma
(Figure 3). In the resection edge of the partial nephrectomy specimen of one of the latter patients (Patient 2), a
CD cell carcinoma was found that had not been recognized on the computed tomographic (CT) scan.
The renal tissue surrounding the tumours showed
dilation of the CD, abundant cyst formation and diffuse
interstitial fibrosis and lymphocytic infiltration. In Patients
2 and 3, not only dilated CD and cysts were seen, but
also papillary projections of the tubular epithelium into
the lumen of several CDs or cysts (Figure 4).
None of the patients had distant metastases on CT
scanning and therapy varied from watchful waiting
because of considerable comorbidity (Patients 4 and 6) to
partial or complete unilateral nephrectomy (Table 1).
Patient 1 became dialysis-dependent after nephrectomy.
None of the patients died from renal malignancy, despite
incomplete removal of a CD cell carcinoma (Patient 2),
extension of the tumour into the perirenal fat (Patient 3),
the presence of a contralateral complicated renal cyst
(Patient 4) or the development of two complicated cysts
in the contralateral kidney after unilateral nephrectomy
(Patient 1). All patients except for one continued the use
of Li because of inadequate psychiatric control on
alternative pharmacotherapy.
Discussion
We report six patients who developed solid renal lesions
of CD origin in the context of chronic Li nephropathy. The
detection of these tumours in six patients among ∼50
patients with chronic Li nephropathy known at our department suggests that Li use predisposes to the development of CD neoplasms. Reports of renal neoplasms in
patients on chronic Li therapy are very rare, and the connection with the use of Li was not made specifically. In a
series of 24 renal biopsies in patients with Li nephropathy, Markowitz et al. [3] reported two tumours, of which
one was a CD cell carcinoma. Because of limited immunohistochemical evaluation, the origin of the other
tumour remained unresolved. In addition, in three unselected histology specimens of humans on Li therapy,
Kjaersgaard et al. [4] described features of typical Li nephropathy in a kidney removed because of an unclassified renal carcinoma.
414
M.B. Rookmaaker et al.
Fig. 2. Immunohistochemistry of the CD cell carcinomas. Cytokeratin 19 (A–D) and vimentin (E–H) staining of CD carcinomas (brown). A, E: Case 1; B, F:
Case 2; C, G: Case 3, D, H: Case 5. Bar represents 50 μm.
Fig. 3. HE staining of renal oncocytomas. Large well-differentiated cells can be seen with eosinophilic granular cytoplasm in Cases 2, 4 and 6 (A–C).
Fig. 4. Cytokeratin 19 staining of the different parts of the same kidney
(Case 3). (A) Normal renal tissue with cytokeratin 19 staining of the CD.
(B) Cyst formation in cytokeratin 19-positive CD. (C) Cytokeratin 19positive papillary structures within the cystic dilated CD. (D) Cytokeratin
19 staining of CD tumour. Bar represents 100 μm.
CD cell carcinomas are derived from principal cells
in the CD. Interestingly, Li can reach very high concentrations in the CD, exceeding that in plasma by 20- to
40-fold [5]. The principal cells in the CD express the
epithelial sodium channel apically which has a
considerable Li permeability, causing high intracellular Li
concentrations [6]. Intracellular Li can inhibit the enzyme
glycogen synthase kinase 3 beta (GSK-3β) by phosphorylation. In agreement with this, cells lining the renal
microcysts in patients on chronic Li therapy contain phosphorylated GSK-3β [4]. GSK-3β regulates the breakdown
of β-catenin; consequently, GSK-3β inhibition increases
the availability of β-catenin. Indeed, it has been shown
that Li increases β-catenin availability in principal cells
[7]. Increased availability of β-catenin in tubular cells is
associated with both increased cell proliferation and cyst
formation [8]. We hypothesize that prolonged stimulation
of principal cell proliferation by Li not only causes cyst
formation, but can also eventually induce adenomas and
carcinomas.
The CD cell carcinomas associated with Li use in our
patients differ from the ‘classical’ CD cell carcinomas. The
latter tumours are rare, with an incidence of less than 2
per 1 000 000 person years [9]. In contrast, the four CD
cell carcinomas in our population of ∼50 patients with Li
nephropathy suggest a much higher incidence in patients
with Li nephropathy. Histologically, the Li-induced tumours
show a more pronounced papillary growth, whereas the
tumour cells do not always retain the hobnail appearance,
typical of classical CD cell carcinomas. In addition, the
lesions found in patients with Li nephropathy tend to occur
multifocally (Patients 1, 2 and 4), which is not surprising in
view of the widespread Li-induced proliferation in CD
throughout both kidneys. Both multifocality and growth
pattern are atypical for classical CD carcinomas. Finally, the
clinical behaviour of the Li-associated CD cell tumours
Solid renal tumours of CD in patients on chronic lithium therapy
appears to be more benign than that of classical CD cell
carcinomas. The latter are aggressive tumours with 80%
lymph node metastases at presentation and a median survival of only 22 months [10]. In contrast, the tumours in
our patients were subclinical, without metastases or recurrences during follow-up.
The pathophysiology of lithium-related oncocytomas
exposure is less straight forward. Oncocytomas are
mostly benign lesions comprising 3–7% of all renal
tumours. Renal oncocytomas are derived from intercalated cells, which do not possess an entry mechanism for
Li. It therefore appears unlikely that Li directly enhances
the proliferation of intercalated cells. However, animal
experiments have shown that Li treatment not only
induces the proliferation of principal cells, but also
causes an increase in the number of intercalated cells,
possibly resulting from proliferation and differentiation of
progenitor cells or the conversion of principal cells into
intercalated cells [1]. Similar mechanisms may be involved in the development of oncocytomas in patients on
Li therapy.
Our data raise the question of whether patients with
chronic Li nephropathy should be screened for renal cysts
and which strategy should be applied in case a complex
cyst or solid tumour is found. A subset of these tumours
are oncocytomas, which are often slow-growing benign
neoplasms that require only surgical intervention in the
case of rapid growth or a large tumour volume [11].
Although the remainder of the Li-induced tumours are
classified as CD cell carcinomas, these tumours appear to
differ from ‘classical’ CD cell carcinomas, specifically with
respect to their clinical behaviour. The benign clinical behaviour challenges the indication for surgery, which
results in loss of renal mass in patients with already compromised renal function. The observation of multifocal Lirelated renal masses in our cases makes the decision to
perform surgery even more difficult. Until more information is obtained on the incidence and natural history
of Li-related proliferative renal disease, we do not
suggest radiological screening in patients with Li nephropathy. In the case of a renal mass found incidentally in a
patient on chronic Li therapy, we would suggest a biopsy.
If an oncocytoma is found, careful radiological follow-up
would be sufficient. If a CD cell carcinoma is found, the
same strategy could be considered in view of the benign
clinical behaviour of the tumours in our cases. However,
treatment should be individualized and surgical removal
may be preferred if a biopsy is technically not feasible,
the tumour grows rapidly or removal of the tumour
would imply only minimal loss of renal mass. Although Li
is often an indispensable drug in patients with psychiatric
disease, we suggest that the use of lithium be stopped in
patients with progressive cystic kidney disease or a
415
complex renal cyst. This suggestion is supported by the
observation that most patients have slowly progressive
renal failure, which in itself forms an indication to stop
the use of Li. Increased awareness of a possible relationship between chronic Li therapy and renal neoplasms will
enhance the knowledge on epidemiology, clinical behaviour and optimal therapy for the Li-related renal
neoplasms.
Conflict of interest statement. None declared.
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Received for publication: 28.6.12; Accepted in revised form: 2.7.12